Giuseppe Gargiulo

EGFR trans-activation by urotensin II receptor is mediated by β-arrestin recruitment and confers cardioprotection in pressure overload-induced cardiac hypertrophy

Urotensin II (UTII) and its seven trans-membrane receptor (UTR) are up-regulated in the heart under pathological conditions. Previous in vitro studies have shown that UTII trans-activates the epidermal growth factor receptor (EGFR), however, the role of such novel signalling pathway stimulated by UTII is currently unknown. In this study, we hypothesized that EGFR trans-activation by UTII might exert a protective effect in the overloaded heart. To test this hypothesis, we induced cardiac hypertrophy by transverse aortic constriction (TAC) in wild-type mice, and tested the effects of the UTII antagonist Urantide (UR) on cardiac function, structure, and EGFR trans-activation. After 7xa0days of pressure overload, UR treatment induced a rapid and significant impairment of cardiac function compared to vehicle. In UR-treated TAC mice, cardiac dysfunction was associated with reduced phosphorylation levels of the EGFR and extracellular-regulated kinase (ERK), increased apoptotic cell death and fibrosis. In vitro UTR stimulation induced membrane translocation of β-arrestin 1/2, EGFR phosphorylation/internalization, and ERK activation in HEK293 cells. Furthermore, UTII administration lowered apoptotic cell death induced by serum deprivation, as shown by reduced TUNEL/Annexin V staining and caspase 3 activation. Interestingly, UTII-mediated EGFR trans-activation could be prevented by UR treatment or knockdown of β-arrestin 1/2. Our data show, for the first time in vivo, a new UTR signalling pathway which is mediated by EGFR trans-activation, dependent by β-arrestin 1/2, promoting cell survival and cardioprotection.

Cerebral embolic lesions detected with diffusion-weighted magnetic resonance imaging following carotid artery stenting: a meta-analysis of 8 studies comparing filter cerebral protection and proximal balloon occlusion.

OBJECTIVESnThe aim of this meta-analysis was to evaluate and compare the efficacy of the 2 different neuroprotection systems in preventing embolization during carotid artery stenting (CAS), as detected by diffusion-weighted magnetic resonance imaging (DW-MRI).nnnBACKGROUNDnData from randomized and nonrandomized studies comparing both types of embolic protection devices revealed contrasting evidence about their efficacy in neuroprotection, as assessed by the incidence of new ischemic lesions detected by DW-MRI.nnnMETHODSnEight studies, enrolling 357 patients, were included in the meta-analysis. Our study analyzed the incidence of new ischemic lesions/patient, comparing filter cerebral protection and proximal balloon occlusion.nnnRESULTSnFollowing CAS, the incidence of new ischemic lesions/patient detected by DW-MRI was significantly lower in the proximal balloon occlusion group (effect size [ES]:xa0-0.43; 95% confidence interval [CI]:xa0-0.84 toxa0-0.02, I(2)xa0= 70.08, Qxa0= 23.40). Furthermore, following CAS, the incidence of lesions at the contralateral site was significantly lower in the proximal protection group (ES:xa0-0.50; 95% CI:xa0-0.72 toxa0-0.27, I(2)xa0= 0.00, Qxa0= 3.80).nnnCONCLUSIONSnOur meta-analysis supports the concept that the use of proximal balloon occlusion compared with filter cerebral protection is associated with a reduction of the amount of CAS-related brain embolization. The data should be confirmed by a randomized clinical trial.

Impact of postoperative acute kidney injury on clinical outcomes after transcatheter aortic valve implantation: A meta-analysis of 5,971 patients

There is conflicting evidence on the safety and efficacy of transcatheter aortic valve implantation (TAVI) in patients with postoperative acute kidney injury (AKI). Therefore, we conducted a meta‐analysis on the impact of AKI on clinical outcomes after TAVI.

Genetic Deletion of Uncoupling Protein 3 Exaggerates Apoptotic Cell Death in the Ischemic Heart Leading to Heart Failure

Background Uncoupling protein 3 (ucp3) is a member of the mitochondrial anion carrier superfamily of proteins uncoupling mitochondrial respiration. In this study, we investigated the effects of ucp3 genetic deletion on mitochondrial function and cell survival under low oxygen conditions in vitro and in vivo. Methods and Results To test the effects of ucp3 deletion in vitro, murine embryonic fibroblasts and adult cardiomyocytes were isolated from wild‐type (WT, n=67) and ucp3 knockout mice (ucp3−/−, n=70). To test the effects of ucp3 genetic deletion in vivo, myocardial infarction (MI) was induced by permanent coronary artery ligation in WT and ucp3−/− mice. Compared with WT, ucp3−/− murine embryonic fibroblasts and cardiomyocytes exhibited mitochondrial dysfunction and increased mitochondrial reactive oxygen species generation and apoptotic cell death under hypoxic conditions in vitro (terminal deoxynucleotidyl transferase‐dUTP nick end labeling–positive nuclei: WT hypoxia, 70.3±1.2%; ucp3−/− hypoxia, 85.3±0.9%; P<0.05). After MI, despite similar areas at risk in the 2 groups, ucp3−/− hearts demonstrated a significantly larger infarct size compared with WT (infarct area/area at risk: WT, 48.2±3.7%; ucp3−/−, 65.0±2.9%; P<0.05). Eight weeks after MI, cardiac function was significantly decreased in ucp3−/− mice compared with WT (fractional shortening: WT MI, 42.7±3.1%; ucp3−/− MI, 24.4±2.9; P<0.05), and this was associated with heightened apoptotic cell death (terminal deoxynucleotidyl transferase‐dUTP nick end labeling–positive nuclei: WT MI, 0.7±0.04%; ucp3−/− MI, 1.1±0.09%, P<0.05). Conclusions Our data indicate that ucp3 levels regulate reactive oxygen species levels and cell survival during hypoxia, modulating infarct size in the ischemic heart.

A meta-analysis of the impact of pre-existing and new-onset atrial fibrillation on clinical outcomes in patients undergoing transcatheter aortic valve implantation.

AIMSnLittle is known about the prognostic role of pre-existing atrial fibrillation (AF) and new-onset AF (NOAF) in transcatheter aortic valve implantation (TAVI). Therefore, the aim of this meta-analysis was to compare the short- and long-term clinical outcomes of patients undergoing TAVI with and without pre-existing and new-onset AF.nnnMETHODS AND RESULTSnTwenty-six studies, enrolling 14,078 patients undergoing TAVI, of whom 33.4% had pre-existing AF and 17.5% had NOAF, were analysed for early and long-term all-cause mortality, cardiovascular mortality and cerebrovascular events (CVE). In patients with pre-existing AF, 30-day all-cause mortality was similar to patients in sinus rhythm (SR). Conversely, long-term all-cause and cardiovascular mortality were significantly greater in pre-existing AF patients than in patients with SR (20 studies; 8,743 patients; HR: 1.68; p<0.00001, and three studies; 1,138 patients; HR: 2.07; p=0.01, respectively). Pre-existing AF was not a predictor of CVE at long-term follow-up. NOAF patients showed similar short- and long-term all-cause mortality when compared to patients in SR, whereas they experienced a significantly higher incidence of CVE at short-term follow-up (six studies; 2,025 patients; HR: 2.86; p<0.00001). A non-significant increase in the incidence of CVE was observed at long-term follow-up.nnnCONCLUSIONSnPre-existing AF is a predictor of all-cause mortality in patients undergoing TAVI. NOAF is related to the occurrence of CVE at short-term follow-up. Similarly to surgical aortic valve replacement (SAVR), the optimal management and risk stratification of these patients should be further investigated.

Increased mortality after transcatheter aortic valve implantation (TAVI) in patients with severe aortic stenosis and low ejection fraction: A meta-analysis of 6898 patients

BACKGROUNDnThere is conflicting evidence regarding the safety and efficacy of transcatheter aortic valve implantation (TAVI) procedures in patients with severe aortic stenosis and low left ventricular ejection fraction (EF). The primary aim of this study was to determine the impact of TAVI on short- and long-term mortality in patients with low EF (EF <50%); the secondary aim was to analyze the impact of TAVI procedure on EF recovery in the same setting of patients.nnnMETHODS AND RESULTSnTwenty-six studies enrolling 6898 patients with severe aortic stenosis undergoing TAVI procedure were included in the meta-analysis and analyzed for 30-day, 6-month and 1-year all-cause and cardiovascular mortality; a further meta-analysis was also performed in patients with low EF to assess EF changes post TAVI. In low EF patients, both all-cause and cardiovascular short- and long-term mortality were significantly higher when compared to patients with normal EF (30-day-all-cause mortality: 0.13; 95% confidence interval [CI]: 0.01 to 0.25, I(2)=49.65, Q=21.85; 1-year-all-cause mortality: 0.25; 95% [CI]: 0.16 to 0.34, I(2)=25.57, Q=16.12; 30-day-cardiovascular mortality: 0.03; 95% [CI]: -0.31 to 0.36, I(2)=66.84, Q=6.03; 1-year-cardiovascular mortality: 0.29; 95% [CI]: 0.12 to 0.45, I(2)=0.00, Q=1.88). Nevertheless, in low EF patients TAVI was associated with a significant recovery of EF, which started at discharge and proceeded up to 1-year-follow-up.nnnCONCLUSIONSnPatients with low EF severe aortic stenosis have higher mortality following TAVI compared to normal EF patients, despite a significant and sustained improvement in EF.

Effects of successful percutaneous lower extremity revascularization on cardiovascular outcome in patients with peripheral arterial disease

BACKGROUNDnLower extremity peripheral arterial disease (LE-PAD) reduces walking capacity and is associated with an increased cardiovascular risk. Endovascular revascularization of LE-PAD improves walking performance and quality of life. In the present study, we determined whether successful lower limbs revascularization also impacts cardiovascular outcome in LE-PAD patients.nnnMETHODSn479 consecutive LE-PAD patients at stage II of Fontaines classification, with ankle/brachial index ≤ 0.90 and one or more stenosis >50% in at least one leg artery, were enrolled in the study. According to the Trans-Atlantic Inter Society Consensus II recommendations, 264 (55.1%) underwent percutaneous lower extremity angioplasty (PTA group), while 215 (44.9%) were managed with conservative therapy (MT group). The incidence of major cardiovascular events (including cardiovascular death, myocardial infarction, ischemic stroke, coronary and carotid revascularizations) was prospectively analyzed by Kaplan-Meier curves. Crude and adjusted HRs (95% CI) of developing a cardiovascular event were calculated by Cox analysis.nnnRESULTSnNo baseline differences were observed among the groups, except for a lower maximum walking distance in the PTA group. During a median follow-up of 21 months (12.0-29.0), the incidence of cardiovascular events was markedly lower in PTA compared to MT patients (6.4% vs. 16.3%; p=0.003), and patients in the MT group showed a 4.1-fold increased cardiovascular risk compared to patients in the PTA group, after adjustment for potential confounders (95% CI 1.22-13.57, p=0.023).nnnCONCLUSIONSnThis study shows that successful revascularization of LE-PAD patients affected by intermittent claudication, in addition to improving functional status, reduces the occurrence of future major cardiovascular events.

Meta-Analysis of Mortality Outcomes and Mitral Regurgitation Evolution in 4,839 Patients Having Transcatheter Aortic Valve Implantation for Severe Aortic Stenosis

Transcatheter aortic valve implantation (TAVI) is an effective alternative therapy in selected patients with severe aortic stenosis. The role and effects of coexistent moderate to severe mitral regurgitation (msMR) in patients who undergo TAVI remain unclear. Thirteen studies enrolling 4,839 patients who underwent TAVI, including patients with msMR, were considered in a meta-analysis and analyzed for all-cause-mortality; a further meta-analysis was performed to assess mitral regurgitation (MR) evolution after TAVI. In patients with msMR, all-cause-mortality after TAVI was significantly increased at 30-day (effect size [ES] -0.18, 95% confidence interval [CI] -0.31 to -0.04, I(2) = 46.51, Q = 7.48), 1-year (ES -0.22, 95% CI -0.36 to -0.08, I(2) = 56.20, Q = 11.41), and 2-year (ES -0.15, 95% CI -0.27 to -0.02, I(2) = 0.00, Q = 2.64) follow-up compared with patients with absent or mild MR, independent of baseline left ventricular ejection fraction. Interestingly, the impact of msMR on outcomes was statistically stronger when the CoreValve system was used. TAVI was also associated with an improvement in MR entity at 3- and 6-month follow-up (overall ES -0.19, 95% CI -0.37 to -0.01, I(2) = 61.52, Q = 10.39). In conclusion, the presence of preoperative msMR in patients with severe, symptomatic aortic stenosis who undergo TAVI negatively affects outcomes after TAVI. In addition, in the same group of patients, a trend toward a reduction in MR severity was observed. Whether the decrease in MR severity affects mortality after TAVI remains to be defined.

Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis

AimsnGut microbiota-derived metabolite trimethylamine-N-oxide (TMAO) is emerging as a new potentially important cause of increased cardiovascular risk. The purpose of this meta-analysis was to systematically estimate and quantify the association between TMAO plasma levels, mortality, and major adverse cardio and cerebrovascular events (MACCE).nnnMethods and resultsnMEDLINE, ISI Web of Science, and SCOPUS databases were searched for ad hoc studies published up to April 2017. Associations between TMAO plasma levels, all-cause mortality (primary outcome) and MACCE (secondary outcome) were systematically addressed. A total of 17 clinical studies were included in the analytic synthesis, enrolling 26u2009167 subjects. The mean follow-up in our study population was 4.3u2009±u20091.5u2009years. High TMAO plasma levels were associated with increased incidence of all-cause mortality [14 studies for 16 cohorts enrolling 15u2009662 subjects, hazard ratio (HR): 1.91; 95% confidence interval (CI): 1.40-2.61, Pu2009<u20090.0001, I2u2009=u200994%] and MACCE (5 studies for 6 cohorts enrolling 13u2009944 subjects, HR: 1.67, 95% CI: 1.33-2.11, Pu2009<u20090.00001, I2u2009=u200946%,). Dose-response meta-analysis revealed that the relative risk (RR) for all-cause mortality increased by 7.6% per each 10u2009μmol/L increment of TMAO [summary RR: 1.07, 95% CI (1.04-1.11), Pu2009<u20090.0001; based on seven studies]. Association of TMAO and mortality persisted in all examined subgroups and across all subject populations.nnnConclusionsnThis is the first systematic review and meta-analysis demonstrating the positive dose-dependent association between TMAO plasma levels and increased cardiovascular risk and mortality.

A Critical Appraisal of Aspirin in Secondary Prevention: Is Less More?

Aspirin represents the sine qua non for antiplatelet pharmacotherapy in patients with cardiovascular diseases because of its well-established role in secondary prevention and its widespread availability and affordability. Historical studies, conducted in an era that bears little resemblance to contemporary clinical practice, demonstrated large reductions in thrombotic risk when aspirin was compared with placebo, thus forming the evidence base promulgated in practice guidelines and recommendations. P2Y12 inhibitors have mostly been studied in addition to aspirin; dual-antiplatelet therapy proved superiority compared with aspirin monotherapy for the prevention of ischemic events, despite increased bleeding risks. An alternative approach currently under investigation includes evaluation of single-antiplatelet therapy with P2Y12 inhibitors alone versus dual-antiplatelet therapy after acute coronary syndromes or coronary stent implantation. As the availability of more effective antiplatelet agents increases, it is time to revisit the existing and long-standing paradigm supporting aspirin use for secondary prevention of atherothrombotic events. Ongoing trials will provide new evidence whether the less-is-more strategy is justified.